Bone & Soft Tissue Pathology
Case 2 -
Osteoblastoma with Secondary ABC
Michael J. Klein
University of Alabama Medical Center
Click on each slide thumbnail image for an enlarged view
This 17-year-old male had begun to complain of pain just above the medial left knee about three months
prior to hospital admission. The pain was first noticed at rest but became so severe that it limited his
daily activities. It interfered with sleep, and it was not relieved by over the counter non-steroidal
anti-inflammatory agents. On physical examination he was a normally developed teenager in obvious
discomfort but not in distress. There was moderate to severe tenderness of the medial knee accompanied
by a sensation of deep soft tissue fullness. Laboratory findings were not remarkable.
Case 2 - Figure 1 - Lateral and AP conventional radiographs demonstrate an ovoid, fairly defined lesion just cephalad to the medial femoral condyle. The lesion is more radiolucent in the middle than at the extremes imparting a somewhat beveled appearance. The AP view suggests that the cortex is focally interrupted medially and that there is an ill-defined soft tissue density outside of the cortex. There is an ovoid, smaller lesion medially with scalloped, sclerotic borders abutting the lateral femoral cortex in the metadiaphyseal region of the femur. In the lateral view, the lesions are superimposed and the scalloped, sclerotic edge of the lateral lesion is more easily seen. In addition, there is slight bulging of the cortex posteriorly
Case 2 - Figure 2 - A fat-suppressed coronal MRI demonstrates that the larger, medial lesion demostrates a mixed signal intensity. Although there is a relatively circumscribed outer edge with low signal, there is a radial high signal surrounding this edge, which may be lesional or edema. The medial edge of the lesion extends through the cortex into a mixed signal soft tissue mass which elevates the periosteum. The second lesion on the lateral side is multilocular and has a circumscribed low signal intensity.. The second coronal view on the left demonstrates the soft tissue mass and emphasizes the high signal about the lesion which extends into the end of the bone
Case 2 - Figure 3 - Two axial fat suppressed T2 weighted views of the distal femur reveal fluid levels in the soft tissue and intraosseous components of the medial lesion and a hypointense signal in the lateral lesion
Case 2 - Figure 4 - Four photomicrographs taken from the curettage at first operation demonstrate a lesion characterized by a very vascular spindle cell and giant cell containing solid tissue (lower left) in which there is a progression from very small complete vessels to partially complete large sinusoids containing blood in their lumens and in their walls (upper left and upper right). In addition, there is bone formation of the periosteal type appreciated at low power outside of the vascular tissue (upper right) as well as bone formation in the walls of the sinusoids (lower right)
Case 2 - Figure 5 - Four additional photomicrographs demonstrate solid areas in which giant cells and vascular tissue can just be appreciated (upper left) and, at higher magnification, the relatively even distribution of the giant cells in the solid areas (lower left) and the hypervascularity of the solid tissue bordering a sinusoid (lower right). The photograph at the upper right, though taken at low power, demonstrates bone formation of reactive type which is partly decalcified (center left) and on the right, more microtrabecular with hemorrhage and background hypercellularity. While the previous seven photographs were typical findings of aneurismal bone cyst, this area looks different at low magnification
Case 2 - Figure 6 - Higher magnification compares solid area of aneurismal bone cyst (lower half) with an area showing more microtrabecular bone with hypercelluarity seen in the last slide (top). Note that this bone is surrounded by appositional nuclei, which represent osteoblasts. In the right photograph, the field is entirely represented by osteoblastic, hypervascular tissue
Case 2 - Figure 7 - On the left is a wedge-shaped curetted fragment of purely osteoblastic tissue with small fragments of ABC. On the right, at high magnification is typical osteoblastoma composed of microtrabeculae surrounded by cells having the characteristics of osteoblasts. A few osteoclast like giant cells are present
Case 2 - Figure 8 - Last photograph at high magnification compares the features of the aneurismal bone cyst component, with an admixture of vessels, spindle cells and multinucleated giant cells (left) with that of osteoblastoma, showing trabecular bone/osteoid surrounded by pear-shaped osteoblasts and multinucleated giant cells (left)
Diagnosis: Osteoblastoma with Secondary ABC
Radiographic studies revealed at least two abnormalities of the distal femur. There was a large
radiolucency with a slightly indistinct upper and lower boundary in the metaphyseal area that did not
seem to extend past the area of the growth plate scar into the epiphysis. The medial cortex was somewhat
indistinct and there was a soft tissue mass associated with a periosteal reaction that was not obviously
continuous. The lateral metaphysis contained an eccentric, radiolucent lesion with scalloped, sclerotic
borders centered in the cortex but probably also involving the cancellous bone. This lesion was
elliptical in shape with its long axis parallel to the long axis of the femur. It was seen more
distinctly in the AP views than in the lateral views where it overlapped with the larger medial lesion.
The second lesion was diagnosed radiographically as fibrous cortical defect/non-ossifying fibroma.
Further imaging studies performed on the patient included an MRI that demonstrated that the soft
tissue extension of the medial lesion was more circumscribed than originally demonstrable by conventional
x-rays. In addition, the expanded extraosseous portion of this mass demonstrated fluid levels best seen
on the axial T2 weighted images, while the signal remained low within the bone.
A clinical diagnosis of telangiectatic osteosarcoma was suspected and an open biopsy was performed
(the section submitted is derived from one of four sections comprising all biopsy materials). Most of
the sections contain an admixture of periosteal new bone, cartilage, and fibrous tissue suggesting a
repair reaction. This repair is superimposed upon a background of tissue composed of spindle cells and
multinucleated giant cells in which a hypervascular, spongy background demonstrating progression from
very small capillary-like structures to large, blood-filled sinusoids sometimes without distinct
endothelium. There is occasionally brisk mitotic activity in the spindle cell component, and scattered
reactive osseous trabeculae. There is no nuclear atypia, pleomorphism, nor atypical mitotic activity.
These findings are characteristic of aneurysmal bone cyst.
In only one of the four sections prepared, (the one handed out) there are two small solid islands of a
tumor composed primarily of differentiating osteoblasts engaged in the bone production. This bone is
wispy and microtrabecular in its orientation. There is no lace-like bone production, no sheet-like bone
production, and no cartilage or fibrous tissue produced by the tumor. The tumor cells resemble
osteoblasts, with eccentric, usually vesicular nuclei, sometimes with a prominent nucleolus, and there is
no increase in nuclear/cytoplasmic ratio and no hyperchromatism. The cytoplasm of the tumor cells is
basophilic to amphophilic. There is scant to minimal mitotic activity in the tumor cells, and no
atypical mitoses are seen. Histologically, this tumor could be either osteoid osteoma or osteoblastoma,
but it was diagnosed as osteoblastoma primarily because of its size on imaging, even though most of the
lesion in these curettings was consistent with aneurysmal bone cyst.
The patient returned to the operating room the following week; a completion curettage revealed
residual aneurysmal bone cyst. There was no evidence of residual osteoblastoma in six sections, which
comprised the entire curetted material.
This case is interesting for several reasons. It is interesting radiographically, because while the
clinical picture was thought to suggest a malignant primary bone tumor such as telangiectatic
osteosarcoma, the process was in fact self-limited and benign. It is also interesting in that this
patient had a distinct and separate benign lesion in the same bone that was not sampled in either of the
curettings. Finally, it is interesting because the secondary aneurysmal bone cyst is so prominent a
feature associated with a different primary benign bone tumor that it completely dominates that lesion
radiographically and histologically.
Jaffe and Lichtenstein originally used the term osteoblastoma independently but Dahlin and Johnson had
previously described the same lesion under the term "giant osteoid osteoma." Although it is identical
histologically to osteoid osteoma, osteoblastoma has a different clinical history, skeletal location, and
growth potential than osteoid osteoma. Osteoblastoma is usually painful, but the pain is not as
disproportionately severe for its size as in osteoid osteoma. In addition, the pain of osteoblastoma is
less often relieved by salicylates and other non-steroidal anti-inflammatory medications as it is with
Osteoblastomas often arise in the axial skeleton. More than one-third of osteoblastomas are found in
the neural arches of the vertebrae. While osteoid osteomas of the spine are associated with painful
scoliosis, osteoblastomas often present with radiculopathies. This may be because osteoid osteomas are
limited to 2 cm or less in diameter, whereas osteoblastomas are usuall 2-4 cm or more in diameter.
Radiographically, there is no absolutely typical pattern for osteoblastoma. It may appear as a
circumscribed radiolucency like osteoid osteoma albeit larger. It may present as a "blown-out" lesion
resembling aneurysmal bone cyst (even if no histological component of aneurysmal bone is identified). It
may even (as in this case), be suggestive of a malignant neoplasm.
Histologically, Osteoblastoma consists of a well-vascularized fibrous stroma showing
prominent osteoblastic differentiation. There are usually wispy immature bone trabeculae with a woven
collagen fiber pattern, and these are often lined by osteoblasts. The cellular stroma even in areas
where there is little bone formation demonstrates osteoblastic differentiation although the osteoblasts
are usually not aggregated into solid sheets. Osteoblasts are pear-shaped with basophilic cytoplasm and
often have enlarged, hyperchromatic nuclei. There are often osteoclasts remodeling trabeculae that are
mineralized, but these are not necessary for the diagnosis. The diagnosis is more difficult if
osteoblastoma reaches a size greater than 4 cm. and particularly, if it is complicated by one or more
recurrences or has a locally more destructive pattern than typical osteoblastoma.
A subset of osteoblastomas has been termed aggressive osteoblastoma. Histologically, they contain
fairly large numbers of so-called epithelioid osteoblasts, which are
polyhedral cells that are at least twice the size of osteoblasts and have prominent nucleoli. In
aggressive osteoblastoma, the osteoblasts not only line the osteoid trabeculae, but they may be disposed
in sheets. It is probable that many lesions that have been reported under the name malignant
osteoblastoma have been instances of particularly aggressive appearing osteoblastomas.
Occasionally, the osteoid formation in osteoblastoma is lace-like, and the mitotic activity is brisk.
Since there are instances of osteoblastoma in which the radiographs are consistent with a malignant tumor
and there are instances in which true osteosarcoma resembles osteoblastoma histologically, it is
sometimes difficult to separate osteoblastoma from osteosarcoma. In general, the degree of nuclear
atypia and mitotic rate is lower in osteoblastoma than in osteosarcoma and atypical mitoses are not found
in osteoblastoma. The interface of lesional tissue and bone is very important diagnostically, because
osteoblastomas are well circumscribed but osteosarcomas resembling osteoblastoma will often permeate the
intertrabecular marrow spaces of normal adjacent bone. The presence of cartilage differentiation,
although it has been rarely reported in osteoblastoma, should always raise the suspicion that the lesion
is osteosarcoma until proven otherwise.
Jaffe and Lichtenstein first mentioned aneurysmal bone cyst (ABC) as a clinical entity in 1942 in
their paper on solitary bone cysts. The term "aneurysmal" alluded to the fact that the lesion is
expansile. Histologically, it is characterized by a spongiform, connective tissue stroma containing
variably dispersed aggregates of osteoclast-like multinucleated giant cells. There are large numbers of
vascular spaces arranged in a progression from very small capillaries to very large sinusoidal pools.
Immunohistochemistry suggests that many of its vascular spaces are incompletely endothelialized, although
its clinical behavior and MRI appearance do not agree with that assessment. Aneurysmal bone cyst tends
to be rich in osteoblastic activity, and reactive bone having prominent appositional osteoblasts is
sometimes so dominant near its sinusoidal walls that ABC can be misdiagnosed as osteoblastoma. This is
an important point in the submitted case, because its histology contains diagnostic features of both
lesions intimately admixed with one another.
The association of ABC with other bone lesions is a well-recognized phenomenon. It has been described
most frequently in combination with the benign bone tumors chondroblastoma, giant cell tumor,
osteoblastoma, and chondromyxoid fibroma. It also occasionally complicates non-ossifying fibroma,
fibrous dysplasia, and other bone lesions, albeit less commonly. In some instances, the ABC reaction is
discovered only on histological examination and not suspected clinically. In many instances, however,
the radiographic appearance suggests ABC and the underlying lesion is discovered admixed with the ABC
dominating the histologic sections. This type of ABC, sometimes referred to as secondary aneurysmal bone
cyst, comprises about half the cases of ABC. Since de novo, or primary ABC
tends to arise prior to the third decade, any lesion thought to be ABC in an individual over the age of
twenty should be examined very carefully for the presence of any other underlying lesion.
While primary ABC may be mistaken for osteoblastoma because of reactive bone formation, ABC may also
be mistaken for giant cell tumor because it can contain extensive fields of randomly dispersed giant
cells in a fibrous stroma. If the patient is skeletally immature (if the growth plates are open), a
diagnosis of giant cell tumor is for all practical purposes ruled out. If the patient is skeletally
mature, a diagnosis of giant cell tumor complicated by ABC is more likely.
The precise assessment of ABC as a distinct disease type is still not settled. Dorfman and Czerniak's
very useful definition is a modern modification of the original description by Jaffe and Lichtenstein; "A
peculiar lesion of bone that is characterized by the presence of spongy or multilocular cystic tissue
filled with blood. The process is benign in nature, but it is locally destructive and has a high
propensity for recurrence. Microscopically, cystic spaces are bordered by septa composed of a well
vascularized, loose, fibroconnective tissue with prominent giant-cell reaction and focal reactive bone
formationů" Although this definition stops short of calling ABC a neoplasm, the clinical behavior it
describes comes tantalizingly close.
Though we may not know for certain under what disease to classify ABC, we have learned
much about its anatomy and physiology from our colleagues in Radiology. Perhaps most interesting about
ABC is that despite the fact that it bleeds at the same rate as a transected vein if unroofed, MRI
demonstrates that blood flow inside an intact ABC is incredibly sluggish. We know this because if a
patient remains motionless during and MRI study, T2 weighted images in the axial and sagittal planes
demonstrate fluid-fluid levels in the locules of the lesion. The fluid above the level is bright signal
and that below the level is signal hypointense; what is happening is sedimentation of erythrocytes from
blood plasma (the plasma is bright on T2 and the erythrocytes do not generate a signal). This
sedimentation of erythrocytes would not take place if blood flow were brisk. It would also never happen
if blood were clotted, or if previously clotted blood were defibrinated. The process requires whole
blood without significant movement, like blood would behave in a glass tube with anticoagulant added.
Since there is no anticoagulant in the locules of ABC, the best logical conclusion is that these spaces
are lined by endothelium since blood not contained within intact endothelial spaces undergoes the
clotting reaction. Although histological and immunochemical studies have not convincingly demonstrated
that the vascular spaces of ABC are completely endothelialized, the lack of in vivo clotting and the
development of fluid levels are the most convincing indirect evidence of this.
While the name aneurysmal bone cyst implies that it is both a cyst and a bone lesion, ABC
may sometimes be neither. Although it was first described in a paper on simple cysts, ABC does not
fulfill the pathological definition of a cyst (i.e., a fluid filled cavity lined by epithelium or a
bladder or sac in the body). A paper by Sanerkin and associates in 1983 describing a series of bone
lesions causing bone expansion that were histologically identical to the cellular solid areas of ABC
without prominent sinusoids only made nomenclature matters worse. The term they used to describe their
lesion, solid aneurysmal bone cyst, is an oxymoron if ABC is a true cyst,
since the terms solid and cyst are mutually exclusive. To further complicate matters, lesions of soft
tissues that are histologically identical to ABC but without having underlying osseous involvement have
been more recently reported. If these lesions are etiologically identical to classical ABC, then even
the term "bone" may also prove incorrect in nomenclature!
Sixty-three years after its first description, a unifying thread is beginning to emerge
with the application of cytogenetic and molecular analyses to ABC. In 1999, Panoutsakapoulos et al.
reported recurrent reciprocal translocations involving chromosomes 16 and 17 in ABC. Subsequent reports
have found translocations between chromosome 17 and several other chromosomes. Most recently, Oliveira
et.al. have linked gene rearrangements of the USP6 and CDH11 oncogenes in ABC using both molecular cytogenetic and molecular genetic
confirmatory techniques. While these rearrangements were not universal (69% of 52 primary ABC's
examined), there were two interesting and perhaps elucidating features. The first is that the gene
rearrangements were present in six of the seven solid variants of ABC examined and in the single soft
tissue example examined. Although the numbers may be small, this provides the first genetic link between
classical, solid, and soft tissue ABC and other evidence besides hematoxylin and eosin sections, that
they may be truly related. The second is that ofanother 17 so-called secondary ABC's tested, there were
no CDH11or USP6 rearrangements detected. This
makes it seem as though so-called secondary ABC, a well recognized occurrence that comprises 50% of ABC
cases, may actually reresent a histologic mimicker of true ABC.
While the radiographs also demonstrate a non-ossifying fibroma in this case, the curetted tissue did
not contain the lesion. Non-ossifying fibroma and fibrous cortical defects, though they are clinically
distinct, are pathologically identical and some pathologists (I am one of these) consider them one and
the same. Together, they constitute the most common space-occupying lesion of bone with an estimated
incidence of 33-40% of growing individuals. For the most part, they are developmental and self-limited
lesions that involute and heal, although the very rare large non-ossifying fibroma will occasionally
undergo pathologic fracture. One in four individuals with fibrous cortical defect have them in more than
a single bone. The most common site is in the most rapidly growing places in the fastest growing bones,
namely, the distal femoral and proximal tibial metaphyses.
Certainly, one in three patients presenting with a primary bone tumor will harbor a non-ossifying
fibroma/fibrous cortical defect in some other bone. Since the same sites that have the highest incidence
of FCD/NOF are also the most common loci of malignant and benign primary bone tumors, it might be
expected that non-ossifying fibroma should be found fairly often as a coincidental entity in the same
bone containing another primary bone tumor. This is, in fact, not the case. There are only eight other
instances of this association reported in the literature; the most common one thus far reported is
non-ossifying fibroma and osteosarcoma.
- Abdelwahab, IF, Klein,MJ, Kenan,S et al: Coexistence of Primary Bone Tumors: Report of 4 Cases of Collision Tumors. JACR 53(5) 296-302, 2002.
- Dahlin, D.C., Johnson,E.W., Jr.: Giant Osteoid Osteoma. JBJS ,36-A, 559, 1954)
- Dorfman,HD, Czerniak,B.: Bone Tumors (St.Louis:Mosby), 1998.
- Dorfman,HD, Weiss,SW: Borderline Osteoblastic Tumors: Problems in the Differential Diagnosis of Aggressive Osteoblastoma and Low-grade Osteosarcoma. Semin Diagn Pathol 1:215-234,1984.
- Jaffe, H.L., Lichtenstein, L.: Solitary Unicameral Bone Cyst. With Emphasis on the Roentgen Picture, the Pathologic Appearance, and the Pathogenesis. Arch surg 44:1004-1025, 1942.
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- Oliveira, A.M., Perez-Atayde, A.R., Inwards,C.Y. et.al.: USP6 and CDH11 Oncogenes Identify the Neoplastic Cell in Primary Aneurysmal Bone Cyst and Are Absent in So-Called Secondary Aneurysmal Bone Cysts. Am Jour Pathol 165:1773-1780, 2004.
- Oliveira, A.M., Bae-Li, H., Weremowicz,S., et.al: USP6 (Tre2) Fusion Oncogenes in Aneurysmal Bone Cyst. Cancer Research 64:1920-1923, 2004.
- Panoutsakapoulos, G., Pandis, N, Kyriazoglou, I. et.al.: Recurrent t(16:17)(q22:p13) in aneurysmal bone cysts. Genes, Chromosomes, Cancer 26:265-266, 1999.
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